We report the case of a 55-year-old woman who presented with hypercortisolism secondary to ectopic adrenocorticotrophic hormone secretion and severe non-thyroidal illness syndrome (NTIS) due to metastatic small cell lung carcinoma associated with severe infections. The patient initially showed hormonal profiles of pituitary hypothyroidism and gonadal hypofunction. After decrease in cortisol production following treatment with chemotherapy and metyrapone, serum thyroid hormones and thyroid-stimulating hormone (TSH) concentrations normalized. Study of the relative contributions of cortisol and pro-inflammatory cytokines (interleukin-6 and tumour necrosis factor α) to the overall variability in thyroid function tests disclosed a significant and independent effect of serum cortisol on serum TSH concentrations; the variability in free thyroid hormone concentration was explained only by changes in TSH concentration. These observations indicate that cortisol could be the major determinant of changes in serum TSH concentrations in clinical conditions accompanied by hypercortisolism, as occurs in NTIS.